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Scott Oakes, MD

Our laboratory is breaking new ground in discovering how various forms of damage trigger death in normal cells and what goes wrong with this process in diseases such as neurodegeneration and cancer—in the hopes of finding new therapeutic targets through which to control the cell’s decision to live or die.

Cell Suicide
All multicellular organisms have evolved mechanisms to silence or eliminate rogue cells that threaten the survival of the majority. As such, human cells are genetically programmed to actively commit “suicide” through a process called apoptosis when they become harmful, superfluous or irreversibly damaged. The final executioners in the apoptotic pathway are a family of proteins called caspases that ultimately digest the cell from the inside out. While great strides have been made in identifying the core apoptotic machinery that dismantles the cell, we still know relatively little about how the process begins. In particular, we are largely ignorant of how cells sense internal damage (say in response to chemotherapy), determine if the damage is lethal, and then relay this information to the apoptotic machinery.

Protein Misfolding, ER Stress and Disease
The endoplasmic reticulum (ER) is the major site within the cell for folding, modification, and trafficking of proteins. Various physiological events (e.g., secretory cell differentiation) and pathological conditions (e.g., hypoxia, nutrient deprivation) can overwhelm the protein folding capacity of the ER. Initially, the stress placed on the ER by an abundance of misfolded protein activates an evolutionarily conserved signal transduction pathway called the unfolded protein response (UPR). The ER-resident transmembrane sensors IRE1α, PERK, and ATF6 are the major effectors of the UPR in mammalian cells, and initially expand the ER network, upregulate chaperones and arrest global translation in order to restore homeostasis. However, if the ER damage is extensive or prolonged, cells initiate apoptosis. Mounting evidence suggests that apoptosis triggered by excessive stress on the protein folding capacity of the ER contributes to pathological cell loss in many common human degenerative diseases, including Alzheimer’s, Parkinson’s, Amyotrophic Lateral Sclerosis, type 2 diabetes, and liver cirrhosis. My long-term goals are to understand how apoptosis occurs in these diseases and to develop strategies to target this pathway for therapeutic benefit. Our laboratory has designed rigorous in vitro assays to detect and isolate several novel apoptotic signals and is tracing them all the way back to the stress sensor proteins at the ER. We are currently designing pharmacological interventions to precisely control and tune these signaling switches with small molecules to influence cell survival.

When Cancer Cells Refuse to Die
Multiple myeloma is a malignant blood cell disorder that accounts for approximately 10% of all hematologic cancers. There will be ~20,000 new cases of myeloma and over 10,000 deaths from the disease in the U.S. alone this year. There are currently more than 50,000 Americans living with myeloma—a number that is expected to substantially increase as the population continues to age. Myeloma remains an incurable disease; however, the prognosis and treatment for a patient diagnosed today are far better than even a few years ago. Unfortunately, all myeloma patients eventually develop resistance to available drugs and succumb to the disease. The molecular basis for this resistance is currently unknown, but recent evidence suggests that myeloma cells have sustained and high levels of cytoprotective signaling through the UPR.

The Oakes lab is applying many of the same techniques described above on primary human myeloma cells to understand how the drugs (such as proteasome inhibitors) trigger apoptosis in sensitive patients and where this process is blocked in resistant cases. This information will be used to design biomarkers to predict patient response to therapy and identify new therapeutic targets in the myeloma cells.